Cisplatin is a highly effective chemotherapeutic agent and widely used for treating solid tumors. However, cisplatin therapy produces serious side effects such as nephrotoxicity, neurotoxicity, and severe ototoxicity. In particular, cisplatin-induced ototoxicity is bilateral and irreversible, and thus particularly serious in the pediatric population and especially during early development to about three years of age. Cisplatin is frequently used to treat cancers like neuroblastoma and CNS neuroblastoma tumors in pediatric patients, but the resulting ototoxicity hampers speech, cognition and social development. Thus, a great need exists for treatments that will ameliorate cisplatin-induced ototoxicity and other side effects in children but also in adults. Carboplatin and oxaliplatin are two other platinum-based chemotherapy agents that have emerged over the last twenty years of intense research aimed at improving cisplatin. Unfortunately, carboplatin and oxaliplatin are effective in treating only a few cancers. Moreover, while oxaliplatin has been used to treat children with central nervous system (CNS) tumors, it has very limited activity (M. Fouladi et al., Phase II study of oxaliplatin in children with recurrent or refractory medulloblastoma, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors: a pediatric brain tumor consortium study, CANCER 107:2291-2297 (2006)), and also consistently produces neuropathies (L. M. Pasetto et al., Oxaliplatin-related neurotoxicity: how and why? CRIT. REV. ONCOL. HEMATOL. 59:159-68 (2006)).
Transplatin (trans-diamminedichloroplatinum (II)), the trans stereoisomer of cisplatin, has the formula trans-[PtCl2(NH3)2] and though well-studied does not exhibit a comparably useful pharmacological effect, though it has been shown to be relatively nontoxic in humans. Although ineffective as an antitumor agent (Coluccia, M., and Natile, G., Trans-platinum complexes in cancer therapy, ANTICANCER AGENTS MED. CHEM. 7:111-123 (2007)), transplatin does not cause ototoxicity at equimolar doses of cisplatin. Its low activity is generally thought to be due to rapid deactivation of the agent before it can interact with the DNA. It is known for instance that transplatin stereochemistry does not allow it to form intrastrand DNA cross-links (Pinto, A. L., and Lippard, S. J., Sequence-dependent termination of in vitro DNA synthesis by cis-and trans-diamminedichloroplatinum (II), PROC. NATL. ACAD. SCI. USA 82:4616-4619 (1985)) formed by cisplatin (cis-DDP). Intrastrand crosslinking of DNA by cisplatin is thought to be the primary DNA adduct underlying cytotoxicity (A. C. Plooy et al., Induction and repair of DNA cross-links in chinese hamster ovary cells treated with various platinum coordination compounds in relation to platinum binding to DNA, cytotoxicity, mutagenicity, and antitumor activity, CANCER RES. 44:2043-2051 (1984)). Cis- and transplatin demonstrate differential DNA-adduct formation, DNA-protein binding and repair mechanisms (R. B. Ciccarelli et al, In vivo effects of cis-and trans-diamminedichloroplatinum (II) on SV40 chromosomes: differential repair, DNA-protein cross-linking, and inhibition of replication, BIOCHEMISTRY 24:7533-7540 (1985)).
Importantly, transplatin rapidly binds to DNA, reaches a maximum at 6 hours, then rapidly decreases over the next 6 hours and continues to decrease over the next 36 hours. In contrast, cisplatin bound DNA continues to increase steadily over 48 hours. For example, it has been shown that the level of cisplatin bound to cellular DNA is approximately 11-fold higher than that of transplatin over a treatment period of 42 hours using equal extracellular concentrations (10 μM) of both the isomers. (T. Saito et al, Similar pharmacokinetics and differential ototoxicity after administration with cisplatin and transplatin in guinea pigs, ACTA LARYNGOL. 117:61-65 (1997)).
A need remains for new approaches to treating or preventing the toxic side effects of effective anti-cancer agents, including those platinum-based chemotherapy agents which are highly effective in cancer therapy, such as cisplatin.